Imidazolyl derivatives

ABSTRACT

The present invention is directed to imidazolyl derivatives of formula (II), wherein the variables are defined in the specification, which are useful as prenyl transeferase inhibitors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of and is a divisionalapplication of U.S. application Ser. No. 09/719,720, filed May 22, 2001now U.S. Pat. No. 6,420,555, which is a con't of U.S. application Ser.No. 09/098,141, filed Jun. 16, 1998, which claims benefits of U.S.application Serial No. 60/089,483, filed Jun. 16, 1998, all of which areincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The present invention is directed to imidazolyl derivatives which areuseful as prenyl transferase inhibitors.

The Ras family of proteins are important in the signal transductionpathway modulating cell growth. The protein is produced in the ribosome,released into the cytosol, and post-translationally modified. The firststep in the series of post-translational modifications is the alkylationof Cys¹⁶⁸ with farnesyl or geranylgeranyl pyrophosphate in a reactioncatalyzed by prenyl transferase enzymes such as farnesyl transferase andgeranylgeranyl transferase (Hancock, J F, et al., Cell 57:1167-1177(1989)). Subsequently, the three C-terminal amino acids are cleaved(Gutierrez, L., et al., EMBO J. 8:1093-1098 (1989)), and the terminalCys is converted to a methyl ester (Clark, S., et al., Proc. Nat'l Acad.Sci. (USA) 85:4643-647 (1988)). Some forms of Ras are also reversiblypalmitoylated on cysteine residues immediately N-terminal to Cys¹⁶⁸(Buss, J E et al., Mol. Cell. Biol. 6:116-122 (1986)). It is believedthat these modifications increase the hydrophobicity of the C-terminalregion of Ras, causing it to localize at the surface of the cellmembrane. Localization of Ras to the cell membrane is necessary forsignal transduction (Willumsen, B M, et al., Science 310:583-586(1984)).

Oncogenic forms of Ras are observed in a relatively large number ofcancers including over 50 percent of colon cancers and over 90 percentof pancreatic cancers (Bos, J L, Cancer Research 49:4682-4689 (1989)).These observations suggest that intervention in the function of Rasmediated signal transduction may be useful in the treatment of cancer.

Previously, it has been shown that the C-terminal tetrapeptide of Ras isa “CAAX” motif (wherein C is cysteine, A is an aliphatic amino acid, andX is any amino acid). Tetrapeptides having this structure have beenshown to be inhibitors of prenyl transferases (Reiss, et al., Cell62:81-88 (1990)). Poor potency of these early farnesyl transferaseinhibitors has prompted the search for new inhibitors with morefavorable pharmacokinetic behavior (James, G L, et al., Science260:1937-1942 (1993); Kohl, N E, et al., Proc. Nat'l Acad. Sci. USA91:9141-9145 (1994); deSolms, SJ, et al., J. Med. Chem. 38:3967-3971(1995); Nagasu, T, et al., Cancer Research 55:5310-5314 (1995); Lerner,E C, et al., J. Biol. Chem. 270:26802-26806 (1995); Lerner, E C, et al.,J. Biol. Chem. 270:26770 (1995); and James, et al., Proc. Natl. Acad.Sci. USA 93:4454 (1996)).

Recently, it has been shown that a prenyl transferase inhibitor canblock growth of Ras-dependent tumors in nude mice (Kohl, N. E., et al.,Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994)). In addition, it hasbeen shown that over 70 percent of a large sampling of tumor cell linesare inhibited by prenyl transferase inhibitors with selectivity overnon-transformed epithelial cells (Sepp-Lorenzino, I., et al., CancerResearch, 55:5302-5309 (1995)).

SUMMARY OF THE INVENTION

In one aspect, this invention provides a compound of formula (I),

or a pharmaceutically acceptable salt thereof,

wherein

———————represents an optional bond;

m, n, p, and q are each independently 0 or 1;

T for each occurrence is independently selected from the groupconsisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

X is N—Y, O or S where Y is selected from the group consisting of H,CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³,C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, cyano, halo, CR¹⁴R¹⁵R¹⁶,S(O)R¹⁷, S(O)₂R¹⁸ and C(O)R¹⁹;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ areeach independently selected from the group consisting of H, halo,hydroxy, thio and cyano, or an optionally substituted moiety selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio,arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or R¹ and R² when on adjacent positions, or R⁴ and R⁵, or R¹¹ and R¹²,are taken together to form a bivalent radical selected from the groupconsisting of —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH═CH—, —O—CH₂—CH₂—,—O—CH₂—CH₂—CH₂— and —CR³³═CR³⁴—CR³⁵═CR³⁶—; R⁷, R⁸ and R⁹ are eachindependently selected from the group consisting of H, halo, aryl,alkyl, substituted alkyl, alkyloxy, alkylthio, aryloxy, arylthio amino,mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl,alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl, arylalkyl andsubstituted arylakyl;

R¹⁰ is selected from the group consisting of H, amino, azido, hydroxy,halo, alkyl, substituted alkyl, cyano, hydroxyalkyl, hydroxycarbonyl,aminoalkyl, mono- or di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy,alkylcarbonylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, carboxyalkyl,cycloalkyl, cycloalkylamino, cycloalkylhydroxy, imidazoyl, substitutedimidazoyl, aminocarbonylalkyl, aryloxy, thio, alkylthio, OS(O₂)R¹⁸,OC(O)R¹⁹, OC(O)NR²⁰R²¹, OC(S)NR²²R²³, OS(O)NR²⁹R³⁰, OS(O)₂NR³¹R³² andarylthio; and R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹,R³⁰, R³¹, R³² and R³⁷ for each occurrence are each independentlyselected from the group consisting of H, alkyl, substituted alkyl,alkenyl, cycloalkyl, aryl and arylalkyl;

or R²⁰ and R²¹, or R²² and R²³, or R²⁹ and R³⁰, or R³¹ and R³² are takentogether to form a bivalent radical selected from the group consistingof —(CH₂)_(r)—NR³⁷—(CH₂)_(s)—, —(CH₂)_(r)—O—(CH₂)_(s)— and—(CR³⁸R³⁹)_(t)—, where r and s are each independently 1 to 3 and t is 2to 6;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ are each independently selected from thegroup consisting of H, halo, cyano, alkyl, substituted alkyl, aryl,substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino,arylamino, hydroxy and thio.

A preferred group of compounds of the immediately foregoing compounds iswhere m, n, p and q are each 0.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹² and R¹³ are each H, halo, alkyl,substituted alkyl, cyano or alkyloxy.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹⁰ is OH, H, halo, azido, amino, mono- or di-alkylamino,OS(O₂)R¹⁸, OC(O)NR²⁰R²¹ or OS(O)₂NR³¹R³².

A preferred group of compounds of the immediately foregoing compounds iswhere R⁷, R⁸ and R⁹ are each H, alkyl, substituted alkyl, amino orcyanoarylalkyl.

A preferred group of compounds of the immediately foregoing compounds iswhere X is N—Y and Y is H, CR¹⁴R¹⁵R¹⁶, S(O)₂R¹⁸, C(O)NR²⁰R²¹ orS(O)₂NR²⁹R³⁰.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹, R², R³, R¹¹, R¹² and R¹³ are each halo or hydrogen.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹, R², R³, R¹¹, R¹² and R¹³ are each chloro or hydrogen.

A preferred group of compounds of the immediately foregoing compounds iswhere R⁷, R⁸, and R⁹ are each (C₁-C₄)alkyl or hydrogen.

A preferred group of compounds of the immediately foregoing compounds iswhere R⁷, R⁸, and R⁹ are each methyl or hydrogen.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹⁰ is OH, amino, OS(O₂)R¹⁸, or OC(O)NR²⁰R²¹.

A preferred group of compounds of the immediately foregoing compounds iswhere R⁴, R⁵ and R⁶ are each H.

A preferred group of compounds of the immediately foregoing compounds iswhere Z is hydrogen.

A preferred group of compounds of the immediately foregoing compounds iswhere Y is H, methyl, S(O)₂R¹⁸, C(O)NR²⁰R²¹ or S(O)₂R²⁹R³⁰.

A preferred group of compounds of the immediately foregoing compounds iswhere said compounds are of the formula:

wherein

R¹⁰ is OH and Y is H;

R¹⁰ is NH₂ and Y is —S(O)₂—CH₃;

R¹⁰ is OH and Y is —S(O)₂—CH₃;

R¹⁰ is OH and Y is —C(O)—N(CH₃)₂;

R¹⁰ is NH₂ and Y is —C(O)—N(CH₃)₂;

R¹⁰ is NH₂ and Y is H;

R¹⁰ is OH and Y is

R¹⁰ is NH₂ and Y is

R¹⁰ is OH and Y is —S(O)₂-Phenyl;

R¹⁰ is NH₂ and Y is —S((O)₂-Phenyl;

R¹⁰ is OH and Y is —C(O)—N(CH₂CH₃)₂;

R¹⁰ is NH₂ and Y is —C(O)—N(CH₂CH₃)₂;

R¹⁰ is OH and Y is —CH₃; and

R¹⁰ is NH₂ and Y is —CH₃.

A preferred group of compounds of the immediately foregoing compounds iswhere said compounds are of the formula

wherein

R¹⁰ is OH and Y is H;

R¹⁰ is NH₂ and Y is —S(O)₂—CH₃;

R¹⁰ is OH and Y is —S(O)₂—CH₃;

R¹⁰ is NH₂ and Y is —S(O)₂—CH₃; and

R¹⁰ is OH and Y is —C(O)—N(CH₃)₂.

A preferred group of compounds of the immediately foregoing compounds iswhere said compounds are of the formula

wherein

R¹⁰ is OH and Y is H; and

R¹⁰ is OH and —S(O)₂—CH₃.

In another aspect, this invention provides a compound of formula (II),

or a pharmaceutically acceptable salt thereof,

wherein

——————— represents an optional bond, provided that only one of theoptional bonds is present in a compound of formula (I);

m, n, p, and q are each independently 0, 1 or 2;

T¹, T², T³ and T⁴ for each occurrence are each independently selectedfrom the group consisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸;

X is N—Y, O or S where Y is selected from the group consisting of H,CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³,C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²;

Z is selected from the group consisting of H, hydroxy, alkoxy, aryloxy,cyano, halo, C¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹,C(O)OR²⁴, C(S)NR²²R²³, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³², providedthat when the optional bond connected to Z is present then Z is oxygenor sulfur;

R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ foreach each independently selected from the group consisting of H, halo,hydroxy, thio and cyano, or an optionally substituted moiety selectedfrom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio,arylthio, alkylamino, arylamino and alkyl carbonyl amino;

or each pair of R¹ and R², R⁴ and R⁵, and R¹¹ and R¹² when on adjacentpositions, is independently taken together to form a bivalent radicalselected from the group consisting of —O—CH₂—O—, —O—CH₂—CH₂—O—,—O—CH═CH—, —O—CH₂—CH₂—, —O—CH₂—CH₂—CH₂— and —CR³³═CR³⁴—CR³⁵═CR³⁶—;

R⁷, R⁸ and R⁹ are each independently H, halo, amino, cyano,hydroxycarbonyl, or an optionally substituted moiety selected from thegroup consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio,alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl andarylalkyl, provided that when R⁷, R⁸ or R⁹ is bound to one of thenitrogen atoms of the imidazolyl ring, R⁷, R⁸ or R⁹ is H or anoptionally substituted moiety selected from the group consisting ofaryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl,cyanoarylalkyl and arylalkyl;

R¹⁰ is selected from the group consisting of H, amino, azido, hydroxy,halo, alkyl, substituted alkyl, cyano, hydroxycarbonyl, mono- ordi-alkylamino, alkyloxy, cycloalkyl, cycloalkylamino, cycloalkyloxy,imidazolyl, substituted imidazolyl, aryloxy, thio, alkylthio, arylthio,OS(O)₂R¹⁸, OC(O)R¹⁹, OC(O)NR²⁰R²¹, OC(S)NR²²R²³, OS(O)NR²⁹R³⁰ andOS(O)₂NR³¹R³²;

R¹⁷ and R¹⁸, for each occurrence are each independently H, OH or anoptionally substituted moiety selected from the group consisting ofalkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;

R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹, R³⁰, R³¹ and R³² for eachoccurrence a independently H or an optionally substituted moietyselected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl,arylalkyl and heterocyclyl;

or each pair of R²⁰ and R²¹, R²² and R²³, R²⁹ and R³⁰, and R³¹ and R³²is independently taken together to form a bivalent radical selected fromthe group consisting of —(CH₂)_(r)—NR⁴⁰—(CH₂)_(s),—(CH₂)_(r)—O—(CH₂)_(s)—, —(CR³⁸R³⁹)_(t)— and—(CH₂)_(r)—NR⁴⁰—(C(O))_(u)—, where r and s are each independently 1 to3, t is 2 to 6 and u is 1 or 2;

R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ for each occurrence are eachindependently selected from the group consisting of H, amino, halo,cyano, alkyl, substituted alkyl, aryl, substituted aryl, alkyloxy,aryloxy, alkylthio, arylthio, mono- or di-alkylamino, arylamino,hydroxy, heterocyclyl and thio;

and R⁴⁰ is H, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴,C(S)OR²⁵, S(O)₂NR³¹R³² or an optionally substituted moiety selected fromthe group consisting of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl andheterocyclyl.

A preferred group of compounds of the immediately foregoing compounds iswhere m, n, p and q are each 0.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹² and R¹³ are each H, halo, alkyl,substituted alkyl, cyano or alkyloxy.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹⁰ is OH, H, halo, azido, amino, mono- or di-alkylamino,OS(O)₂R¹⁸, OC(O)NR²⁰R²¹ or OS(O)₂NR³¹R³².

A preferred group of compounds of the immediately foregoing compounds iswhere R⁷, R⁸ and R⁹ are each H, alkyl, substituted alkyl orcyanoarylalkyl.

A preferred group of compounds of the immediately foregoing compounds iswhere X is N—Y and Y is H, CR¹⁴R¹⁵R¹⁶, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹,C(O)OR²⁴ or S(O)₂NR³¹R³².

A preferred group of compounds of the immediately foregoing compounds iswhere R¹, R², R³, R¹¹, R¹² and R¹³ are each halo or H.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹, R², R³, R¹¹, R¹² and R¹³ are each chloro or H.

A preferred group of compounds of the immediately foregoing compounds iswhere R⁷, R⁸, and R⁹ are each (C₁-C₄)alkyl or H.

A preferred group of compounds of the immediately foregoing compounds iswhere R⁷, R⁸, and R⁹ are each methyl or H.

A preferred group of compounds of the immediately foregoing compounds iswhere R¹⁰ is OH, amino, OS(O)₂R¹⁸, OC(O)NR²⁰R²¹ or OS(O)₂NR³¹R³².

A preferred group of compounds of the immediately foregoing compounds iswhere R⁴, R⁵ and R⁶ are each H.

A preferred group of compounds of the immediately foregoing compounds iswhere Z is hydrogen, halo or C(O)NR²⁰R²¹.

A preferred group of compounds of the immediately foregoing compounds iswhere Y is H, methyl, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(O)OR²⁴ orS(O)₂NR³¹R³².

A preferred group of compounds of the immediately foregoing compounds iswhere said compounds are of the formula:

wherein

Z is H, R¹⁰ is OH and Y is H;

Z is H, R¹⁰ is NH₂ and Y is —S(O)₂—CH₃;

Z is H, R¹⁰ is OH and Y is —S(O)₂—CH₃;

Z is H, R¹⁰ is OH and Y is —C(O)—N(CH₃)₂;

Z is H, R¹⁰ is NH₂ and Y is —C(O)—N(CH₃)₂;

Z is H, R¹⁰ is NH₂ and Y is H;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is —S(O)₂-Phenyl;

Z is H, R¹⁰ is NH₂ and Y is —S(O)₂-Phenyl;

Z is H, R¹⁰ is OH and Y is —C(O)—N(CH₂CH₃)₂;

Z is H, R¹⁰ is NH₂ and Y is —C(O)—N(CH₂CH₃)₂;

Z is H, R¹⁰ is OH and Y is —CH₃;

Z is H, R¹⁰ is NH₂ and Y is —CH₃;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is —C(O)—CH₃;

Z is H, R¹⁰ is NH₂ and Y is —C(O)—CH₃;

Z is H, R¹⁰ is OH and Y is —S(O)₂—CF₃;

Z is H, R¹⁰ is NH₂ and Y is —S(O)₂—CH₂—CF₃;

Z is H, R¹⁰ is OH and Y is —S(O)₂—CH₂—CF₃;

Z is H, R¹⁰ is NH₂ and Y is —S(O)₂—CH₂—CF₃;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is —C(O)—NH₂;

Z is H, R¹⁰ is NH₂ and Y is —C(O)—NH₂;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂and Y is

Z is Cl, R¹⁰ is NH₂ and Y is

Z is Cl, R¹⁰ is NH₂ and Y is —S(O)₂—CH₃;

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂ and Y is

Z is H, R¹⁰ is OH and Y is

Z is H, R¹⁰ is NH₂and Y is

A preferred group of compounds of the immediately foregoing compounds iswhere said compounds are of the formula:

wherein

Z is H, R¹⁰ is OH and Y is H;

Z is H, R¹⁰ is NH₂ and Y is —S(O)₂—CH₃;

Z is H, R¹⁰ is OH and Y is —S(O)₂—CH₃;

Z is H, R¹⁰ is OH and Y is —C(O)—N(CH₃)₂;

Z is H, R¹⁰ is OH and Y is —C(O)—CH₃; and

Z is H, R¹⁰ is NH₂ and Y is —C(O)—CH₃.

In another aspect, this invention provides a pharmaceutical compositioncomprising an effective amount of a compound of formula (I) or (II), asdefined hereinabove, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

In yet another aspect, this invention provides a method of treating atumor, fibrosis or restenosis in a subject in need thereof, whichcomprises administering to said subject an effective amount of acompound of formula (I) or (II), as defined hereinabove, or apharmaceutically acceptable salt thereof.

In still another aspect, this invention provides a method of inhibitingprenyl transferase in a subject in need thereof, which comprisesadministering to said subject an effective amount of a compound offormula (I) or (II), as defined hereinabove, or a pharmaceuticallyacceptable salt thereof.

In yet another aspect, the present invention is directed to a processfor synthesizing a compound of formula 3, according to the scheme below,which comprises reacting a compound of formula 1, according to thescheme below, with an arylalkylmagnesium chloride of formula 2,according to the scheme below, in which case X³ is Cl—Mg and p=1-2, oran aryllithium of formula 2, in which case X³ is Li and p=0, in an inertorganic solvent, until the reaction is substantially complete,

wherein P is a protecting group and the other substituents are asdefined for the compound of formula (II) hereinabove.

In still another aspect, the present invention is directed to a processfor synthesizing a compound of formula 2, according to the scheme below,which comprises reacting a compound of formula 1, according to thescheme below, with a chlorinating reagent until the reaction issubstantially complete,

wherein the substituents are as defined for the compound of formula IIhereinabove.

In an even further aspect, the present invention is directed to aprocess for synthesizing a compound of formula 3, according to thescheme below, which comprises reacting a compound of formula 2 withanhydrous liquid ammonia or an inert organic solvent saturated withanhydrous ammonia when n, p and q are each 0, or ammonium hydroxide whenn, p and q are each not 0, until the reaction is substantially complete

wherein the substituents are as defined for the compound of formula (II)hereinabove.

DETAILED DESCRIPTION

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

In the portion of the compound of formula (I) or (II), where the twooptional bonds are shown, only one of the optional bonds may be presentin a compound. When the optional bond directly attached to the variableZ is present then Z is an oxygen or sulfur.

The term “alkyl” refers to straight or branched chain unsubstitutedhydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbonatoms.

The term “substituted alkyl” refers to an alkyl group substituted by,for example, one to four substituents, such as, halo, hydroxy, alkoxy,oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino,aralkylamino, disubstituted amines in which the 2 amino substituents areselected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino,aralkanoylamino, substituted alkanoylamino, substituted arylamino,substitituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl,aralkylsulfonyl, sulfonamido, e.g. SO₂NH₂, substituted sulfonamido,nitro, cyano, carboxy, carbamyl, e.g. CONH₂, substituted carbamyl e.g.CONH alkyl, CONH aryl, CONH aralkyl or cases where there are twosubstituents on the nitrogen selected form alkyl, aryl or aralkyl;alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, suchas indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl and the like. Where noted above where the substituent isfurther substituted it will be with alkyl, alkoxy, aryl or aralkyl.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “aryl” refers to monocyclic or bicyclic aromatic group having 6to 12 carbon atoms in the ring portion such as phenyl, naphthyl,biphenyl and diphenyl, each of which may be substituted.

The term “arylalkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “substituted aryl” refers to an aryl group substituted by, forexample, one to five substituents such as alkyl; substituted alkyl,halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl,alkanoyloxy, amino, alkylamino, arylalkylamino, arylalkylamino,dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano,carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono,arylthiono, alkylsulfonyl, sulfonamido, aryloxy and the like. Thesubstituent may be further substituted by hydroxy, alkyl, alkoxy, aryl,substituted aryl, substituted alkyl, or arylalkyl.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having one to four double bonds.

The term “substituted alkenyl” refers to an alkenyl group substitutedby, for example, one to three substituents, such as, aryl, substitutedaryl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino,dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono,alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substitutedcarbamyl, guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl,pyrrolidyl pyridyl, pyrimidyl and the like.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having one to four triple bonds.

The term “substituted alkynyl” refers to an alkynyl group substitutedby, for example, a substituent, such as, halo, hydroxy, alkoxy,alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino,thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano,carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g.imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyland the like.

The term “cycloalkyl” refers to an optionally substituted, saturatedcyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and3 to 7 carbons per ring which may be further fused with an unsaturatedC3-C7 carbocyclic ring. Exemplary groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents includeone or more alkyl groups as described above, or one or more groupsdescribed above as alkyl substituents.

The terms “heterocycle”, heterocyclic and “heterocyclyl” refer to anoptionally substituted, fully saturated or unsaturated, aromatic ornon-aromatic cyclic group, for example, which is a 4 to 7 memberedmonocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclicring system, which has at least one heteroatom. Each ring of theheterocyclic group containing a heteroatom may have 1, 2, 3, 4 or 5heteroatoms selected from nitrogen, oxygen and sulfur, where thenitrogen and sulfur heteroatoms may also optionally be oxidized and thenitrogen heteroatoms may also optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl,isothiazolidinyl, thietanyl, thiiranyl, triazinyl, tetrazolyl andtriazolyl, and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl) orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazoliny (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxaxolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like.

Exemplary substituents include one or more alkyl groups as describedabove or one or more groups described above as alkyl substituents. Alsoincluded are smaller heterocycles, such as, epoxides and aziridines.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

A compound of formula (I) or (II) may form pharmaceutically acceptablesalts which are also within the scope of this invention.Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable)salts are preferred, although other salts are also useful, e.g., inisolating or purifying the compounds of this invention.

A compound of formula (I) or (II) may form salts with alkali metals suchas sodium, potassium and lithium, with alkaline earth metals such ascalcium and magnesium, with organic bases such as dicyclohexylamine,tributylamine, pyridine and amino acids such as arginine, lysine and thelike. Such salts may be obtained, for example, by exchanging thecarboxylic acid protons, if they contain a carboxylic acid, with thedesired ion in a medium in which the salt precipitates or in an aqueousmedium followed by evaporation. Other salts can be formed as known tothose skilled in the art.

A compound of formula (I) or (II) may form salts with a variety oforganic and inorganic acids. Such salts include those formed withhydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuricacid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonicacid, toluenesulfonic acid and various others (e.g., nitrates,phosphates, tartrates, citrates, succinates, benzoates, ascorbates,salicylates and the like). Such salts may be formed by reacting acompound of formula (I) or (II) in an equivalent amount of the acid in amedium in which the salt precipitates or in an aqueous medium followedby evaporation.

As is well known to those skilled in the art, the known and potentialuses of prenyl transferase inhibitors are varied and multitudinous, suchas for treating restenosis or a tissue proliferative disease. Examplesof tissue proliferative disease include both those associated withbenign cell proliferation such as fibrosis, benign prostatichyperplasia, atherosclerosis and restenosis; and those associated withmalignant cell proliferation such as cancer (e.g., ras mutant tumors).Examples of such tumors include breast, colon, pancreas, prostate, lung,ovarian, epidermal and hematopoietic cancers (Sepp-Lorenzino, I, et al.,Cancer Research, 55:5302, 1995). Other diseases and conditions thatprenyl transferase inhibitors can be used for is in the treatment ofneoplasm, fungal infection, arteriosclerosis, retina disease, hepatitis,renal disease, myeloid leukemia, viral infection, nervous system tumorand viral infection.

Accordingly, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one of the compounds of Formula I in association with apharmaceutically acceptable carrier.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection, or implant), nasal, vaginal, rectal, sublingual or topicalroutes of administration and can be formulated with pharmaceuticallyacceptable carriers to provide dosage forms appropriate for each routeof administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than suchinert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, the elixirscontaining inert diluents commonly used in the art, such as water.Besides such inert diluents, compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil andcornoil, gelatin, and injectable organic esters such as ethyl oleate.Such dosage forms may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. They may be sterilized by,for example, filtration through a bacteria-retaining filter, byincorporating sterilizing agents into the compositions, by irradiatingthe compositions, or by heating the compositions. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustainedrelease composition such as those described in the following patents.U.S. Pat. No. 5,672,659 teaches sustained release compositionscomprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760teaches sustained release compositions comprising a bioactive agent in agelable form. U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997,teaches polymeric sustained release compositions comprising a bioactiveagent and chitosan. U.S. application Ser. No. 08/740,778 filed Nov. 1,1996, teaches sustained release compositions comprising a bioactiveagent and cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan.29, 1998, teaches absorbable sustained release compositions of abioactive agent. The teachings of the foregoing patents and applicationsare incorporated herein by reference.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. Generally, dosagelevels of between 0.0001 to 100 mg/kg of body weight daily areadministered to humans and other animals, e.g., mammals, to obtaineffective release of growth hormone.

A preferred dosage range is 0.01 to 100.0 mg/kg of body weight dailywhich can be administered as a single dose or divided into multipledoses.

A compound of formula (I) or (II) can be tested for activity as aninhibitor of prenyl transferase according to the following in vitroassay.

Farnesyl transferase activity is assayed by [³H] farnesylation ofrecombinant human H-Ras protein wild type, using microplate andfiltration method. Incubation mixture contains, in a total volume of 25μl: 50 mM Tris HCl (pH 7.5), 5 mM dithiothreitol, 20 μM ZnCl₂, 40 mMMgCl₂, 0.6 μM [³H] farnesyl pyrophosphate (22.3 Ci/mmol), 4 μM H-Ras and10 μg of farnesyl transferase from human brain cytosol. Test compoundsare added in adequate solvent and incubations start by addition offarnesyl transferase. After approximately 60 minutes at approximately37° C., the reaction is stopped by addition of 100 μl of 10% HCl inethanol and allowed to incubate approximately 15 minutes atapproximately 37° C., then 150 μl of absolute ethanol are added andincubation mixture is filtered on Unifilter GF/B microplates and washed6 times with ethanol. After addition of 50 μl of Microscint 0, plateswere counted on a Packard Top Count scintillation counter.Geranylgeranyl transferase activity is assayed by the same method, butusing 4 μM human recombinant H-Ras CVLL type, 0.6 μM [³H]geranylgeranyl-pyrophosphate (19.3 Ci/mmol) and 100 μg ofgeranylgeranyltransferase from human brain.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference.

The compounds of the present invention can be made according to thefollowing schemes and associated descriptions and by methods well-knownto those of ordinary skill in the art. The starting materials andreagents are either commercially available or can be synthesizedaccording to published procedures well-known to those of ordinary skillin the art. The substituents have the same definitions as for thecompound of formula (II), shown hereinabove.

This reaction is accomplished by the reaction of an aldehyde or ketoneof formula 1 with a phenylhydrazine of formula 2 in a mixed acid/organicsolvent or an acid solvent, such as acetic acid at an elevatedtemperature, preferably at reflux temperatures.

Step 1

In Scheme 2, starting material 1 has a protecting group, P¹, such as aphenylsulfonyl or methylsulfonyl group, at position 1 of the indolering. An indole of formula 1 is treated in an organic solvent, such astetrahydrofuran, with active zinc at about room temperature to give3-indolylzinc iodide 2.

Step 2

Thereafter product 2 is coupled with an iodo- or bromo-aromatic system 3(X¹=l or Br), such as iodobenzene in the presence of a catalyst, such astetrakis(triphenylphosphine)palladium in an organic solvent at aboutroom temperature.

Step 3

Thereafter product 3 is hydrolyzed by using an appropriate base, such asKOH or NaOH in a suitable solvent, such as methanol at from about 0° C.to about 100° C. This step may also be accomplished by treating withtetraalkylammonium fluoride, such as tetrabutylammonium fluoride in asuitable organic solvent, such as tetrahydrofuran, at an elevatedtemperature, preferably reflux temperatures.

Step 1

In Scheme 3, compound 1 is reduced by using an appropriate reducingagent, such as borane in an organic solvent containing a suitable acid,such as tetrahydrofuran containing trifluoroacetic acid at from about 0°C. to about room temperature.

Step 2

Thereafter product 2 is protected by reacting with an appropriate agent,such as methanesuffonyl chloride, ρ-toluenesulfonyl chloride orphenylsulfonyl chloride in the presence of a base, such as triethylamineor N,N-diisopropylethylamine in an inert organic solvent, such asdichloromethane or N,N-dimethylformamide at from about −78° C. to aboutroom temperature.

Step 3

Thereafter product 3 is coupled with the chloride acid 4 in the presenceof an acid or Lewis acid, such as aluminum chloride, in a solvent, suchas carbon disulfide or dichloromethane at from about −78° C. to anelevated temperature such as 100° C.

In Scheme 4, compound 1 is oxidized by reacting it with an oxidizingagent, for example, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone ormanganese (III) acetate dihydrate in an organic solvent, such as dioxaneor acetic acid from about room temperature to about 150° C.

In Scheme 5, compound 1 which has an iodo- or bromo-substituent atposition 2 (X²=I or Br) is reacted with an alkyne 2 in the presence of asuitable catalyst, such as palladium(II) acetate, an appropriate basesuch as potassium carbonate and other agents which are necessary for thereaction, such as triphenylphosphine/lithium chloride in an organicsolvent, such as N,N-dimethylformamide at from about room temperature toabout 150° C.

Step 1

In scheme 6, compound 1 is treated with nitrous acid in a solvent, suchas water or sulfuric acid at from about 0° C. to 50° C.

Step 2

Thereafter product 2 is reacted with compound 3 in the presence of asuitable base, such as potassium hydroxide in a solvent such as water atabout 0° C. The mixture is treated with an acid, such as ethanolichydrogen chloride at from about 50° C. to about 80° C.

Step 1

In Scheme 7, compound 1 is hydrolyzed by reacting with a base, such aspotassium hydroxide or sodium hydroxide in a solvent mixture, such aswater/ethanol or a solvent, such as ethanol or water at an elevatedtemperature, preferably at reflux temperatures.

Step 2

Thereafter product 2 is reacted with a primary or secondary amine in thepresence of a coupling agent such as2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateand a base, such as dilsopropylethylamine in an organic solvent, such asN,N-dimethylformamide at from about 0° C. to about room temperature.

In Scheme 8, the reaction is accomplished by reacting 1 with anappropriate decarboxylating agent, such as quinoline/copper at anelevated temperature, preferably at reflux temperatures to obtain acompound of formula 2.

Step 1

In Scheme 9, compound 1 is reduced by reacting with a suitable reducingagent, such as sodium borohydride in a suitable organic solvent, such asether or tetrahydrofuran, yielding intermediate 2.

Step 2

Thereafter product 2 is reacted with an appropriate reagent, such asthionyl chloride or methanesulfonyl chloride to convert the hydroxygroup into an active leaving group, such as chloro- or methylsulfonategroup (L¹=Cl or CH₃S(O)₂O—).

Step 3

Thereafter product 3 is reacted with an imidazole of formula 4 in thepresence of a suitable base, such as potassium carbonate in an organicsolvent, such as acetonitrile at an elevated temperature, preferably atreflux temperatures. If the optional protecting group P is not stableunder the reaction condition and hydrolyzed, another additional step maybe needed to introduce the Y group at the nitrogen in the indole ring.If this additional step is required, the intermediate is treated withY—L, in which L is an active leaving group, for example Y—Cl, e.g.,methanesulfonyl chloride or dimethylcarbamoyl chloride, in an inertorganic solvent at from about −78° C. to about room temperature.

In Scheme 10, compound 1 is reacted with an imidazole of formula 2, inwhich R⁷ is an optional protective group, such as a dimethylaminosulfonyl group, which can be removed after the addition. The reactiontakes place in the presence of a suitable base, such as butyl lithium.If R⁸ is hydrogen at position 2 of the imidazole then it needs to betemporarily protected with a protecting group, such as triethylsilane byreacting it with an appropriate reagent, such as chlorotriethylsilane.If the optional protective group P, such as a methylsulfonyl group isnot stable under the reaction condition and cleaved off, another reagentwhich can introduce a Y group at the nitrogen of the indole ring, forexample Y—Cl, e.g., methanesulfonyl chloride or dimethylcarbamoylchloride, may be added into the reaction mixture to obtain the desiredcompound 3. The chlorotriethylsilyl group is hydrolyzed during thework-up procedure.

In Scheme 11, compound 1 is reacted with an arylalkylmagnesium chloride(X³=Cl—Mg, p=1-2) or an aryllithium (X³=Li, p=0) shown as compound 2, inan inert organic solvent, such as tetrahydrofuran. If the optionalprotective group P, is not stable under the reaction condition andcleaved off, another reagent which can introduce a Y group at thenitrogen of the indole ring, for example Y—Cl, e.g., methanesulfonylchloride or dimethylcarbamoyl chloride, may be added into the reactionmixture to obtain the desired compound 3.

Step 1

In Scheme 12, the first reaction is accomplished by the reaction of analdehyde or ketone of formula 1 with a phenylhydrazine or its derivativeof formula 2 in a mixed acid/organic solvent or an acid solvent, such asacetic acid at an elevated temperature, preferably at reflextemperature.

Step 2

Thereafter product 3 is reacted with Y—L, in which L is an activeleaving group, such as a chloride group, in the presence of a suitablebase, such as triethylamine or diisopropylethylamine in an inert organicsolvent, such as dichloromethane or N,N-dimethylformamide at from about−78° C. to about room temperature.

Step 3

Thereafter product 4 is converted into alkyl- (n=1 or 2) orarylmagnesium (n=0, M=MgX³, in which X³=halide, e.g., Cl or Br) halideor alkyl-(n=1 or 2) or aryl-(n=0, M=Li) lithium by reacting withmetallic magnesium, lithium metal or alkyllithium, such as butyllithiumin an inert organic solvent, such as ether or tetrahydrofuran at about−12° C. to about room temperature.

Step 4

Thereafter product 5 is reacted with ketone 6 in an inert organicsolvent, such as ether or tetrahydrofuran at from about −12° C. to aboutroom temperature.

Step 1

In Scheme 13, starting material 1 is reduced by reacting with a reducingagent, such as borane in an organic solvent, such as tetrahydrofurancontaining an acid, such as trifluoroacetic acid at from about 0° C. toabout room temperature.

Step 2

Thereafter product 2 is reacted with Y—L, in which L is an activeleaving group, such as a chloro group, in the presence of a suitablebase, such as triethylamine or diisopropylethylamine in an organicsolvent, such as dichloromethane or N,N,-dimethylformamide at from about−78° C. to about room temperature, yielding compound 3.

Step 3

Thereafter product 3 is converted into alkyl-(n=1 or 2) or arylmagnesium(n=0, M=MgX⁵, in which X⁵=halide, e.g., Cl or Br) halide or alkyl-(n=1or 2) or aryl-(n=0) lithium (M=Li) by reacting with metallic magnesium,lithium metal or alkyllithium, such as butyllithium in an inert organicsolvent, such as ether or tetrahydrofuran at about −12° C. to about roomtemperature.

Step 4

Thereafter product 4 is reacted with ketone 5 in an inert organicsolvent, such as ether or tetrahydrofuran at from about −12° C. to aboutroom temperature.

In Scheme 14, compound 1 can be converted to compound 2 by reacting witha suitable group of reagents, such as methyl sulfoxide/concentrated HClor potassium persulfate/sodium acetate in a suitable solvent such aswater or an alcohol.

In Scheme 15, compound 1 can be convened to compound 3 by reacting withcompound 2 in the presence of suitable base.

In Scheme 16, compound 1 can be converted to compound 3 by reacting itwith compound 2 under suitable conditions.

Step 1

In Scheme 17, compound 1 is converted to compound 2, in which P⁴—O— isan active leaving group, such as methylsulfonate, p-toluenesulfonate ortrifluoromethanesulfonate by reacting it with a suitable reagent, suchas methanesulfonyl chloride, ρ-toluenesulfonyl chloride ortrifluoromethanesulfonic anhydride in an inert organic solvent, such asdichloromethane.

Step 2

Thereafter product 2 is reacted with sodium azide to yield compound 3 inan organic solvent, such as N,N-dimethylformamide at from about roomtemperature to an elevated temperature, such as about 60° C.

Step 3

Thereafter product 3 is reduced to compound 4 by reacting it with anappropriate reducing agent, such as triphenylphosphine with water in asuitable solvent such as pyridine.

Step 1

In Scheme 18, compound 1 can be converted to compound 2 which has anactive leaving group, such as a chloro group, by reacting with anappropriate reagent, such as thionyl chloride at from about roomtemperature to an elevated temperature, preferably at about 38° C.

Step 2

Thereafter product 2 is reacted with an appropriate agent, such asliquid ammonia at from low temperature, such as −78° C., to an elevatedtemperature.

EXAMPLE 1(±)-3-(3-Chlorophenyl)-5-[(4-chlorophenyl)hydroxyl(1-methyl-1H-imidazol-5-yl)methyl]Indole

To a solution of 1-methylimidazole (53 mg) in anhydrous THF (3 mL) wasadded dropwise a solution of butyllithium in hexane (1.6 M, 430 μL) atabout −78° C. The mixture was stirred at about −78° C. for about 15minutes. To the solution was added dropwise a solution ofchlorotriethylsilane in THF (1.0M, 660 μL). The mixture was warmed toroom temperature and stirred at room temperature for 1 hour. The mixturewas cooled to about −78° C. and to it was added dropwise a solution ofbutyllithium in hexane (1.6M, 430 μL). The solution was stirred at about−78° C. for about 1 hour and in the following 15 minutes, it was warmedto about −15° C. The solution was cooled to about −78° C. To it wasadded dropwise a solution of1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (95 mg)(see preparation #7) in THF (2 mL). The mixture was warmed to roomtemperature and stirred for about 2 hours. The solution was cooled toabout 0° C. and to it was added methanol and water. The mixture wasstirred for about 2 hours. The solution was concentrated in vacuo. Theresidue was dissolved in dichloromethane (DCM) and washed with wateronce. The organic layer was dried over anhydrous MGSO₄, filtered, andconcentrated in vacuo. The crude product was purified by columnchromatography, on silica, eluting with DCM/MeOH 95:5. Affording thetitle compound Rf=0.20 (silica, DCM/MeOH 9:1), MS (ES) 447.2; Calc.MW=447.4. 60 mg, yield: 63%.

Alternatively, the compound of Example 1,(±)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indolecan be synthesized according to the following procedure. To a solutionof 1-methylimidazole (53 mg) in anhydrous THF (3 mL) was added dropwisea solution of butyllithium in hexane (1.6 M, 430 μL) at about −78° C.The mixture was stirred at about −78° C. for about 15 minutes. To thesolution was added dropwise a solution of chlorotriethylsilane in THF(1.0M, 660 μL). The mixture was warmed to room temperature and stirredat room temperature for about 1 hour. The mixture was cooled to about−78° C. and to it was added dropwise a solution of butyllithium inhexane (1.6M, 430 μL). The solution was stirred at about −78° C. forabout 1 hour and in the following 15 minutes, it was warmed to about−15° C. The solution was cooled to about −78° C. To it was addeddropwise a solution of1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline (95 mg)(see preparation #6) in THF (2 mL). The mixture was warmed to roomtemperature and stirred for about 2 hours. The solution was cooled toabout 0° C. and to it was added methanol and water. The mixture wasstirred for about 2 hours. The solution was concentrated in vacuo. Theresidue was dissolved in dichloromethane (DCM) and washed with wateronce. The organic layer was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel eluting with DCM/MeOH 95:5, affording thetitle compound.

The enantiomers of the title compound can be separated by usingtechniques known in the art, such as prep HPLC over a chiral column.

EXAMPLE 2(±)-1-Methylsulfonyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole

To a solution of 1-methylimidazole (88 mg) in anhydrous THF (3 mL) wasadded dropwise a solution of butyllithium in hexane (1.6 M, 694 μL) atabout −78° C. The mixture was stirred at about −78° C. for about 15minutes. To the solution was added dropwise a solution ofchlorotriethylsilane in THF (1.0 M, 1.08 mL). The mixture was warmed toroom temperature and stirred for about 1 hour. The solution was cooledto about −78° C. To it was added dropwise a solution of butyllithium inhexane (1.6 M, 694 μL). The mixture was stirred at about −78° C. forabout 1 hour and then warmed to about −15° C. It was stirred at about−15° C. for about 15 minutes. The solution was cooled to about −78° C.To the solution was added dropwise a solution of1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline (150 mg)(see preparation #6) in THF (2 mL). The mixture was warmed to roomtemperature and stirred for about 2 hours. The solution was cooled toabout −78° C. To it was added dropwise methanesulfonyl chloride (116mg). The solution was slowly warmed to room temperature and stirredovernight. The solution was cooled to about 0° C. To it was added waterand stirred for about 2 hours. The solution was diluted with DCM and theorganic layer was separated and concentrated in vacuo. The crude productwas purified by column chromatography on silica, eluting with CHCl₃/MeOH95:5 affording the title compound as a solid. MS (ES): 525.1; Calc.MW=525.5. 30 mg, yield: 17%.

Alternatively, the compound of Example 2,(±)-1-Methylsulfonyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indolecan be synthesized according to the following procedure.

To a solution of 1-methylimidozole (88 mg) in anhydrous THF (1.5 mL) wasadded dropwise a solution of butyllithium in hexane (1.6M, 694μL) atabout −78° C. The mixture was stirred at about −78° C. for about 30 min.To the solution was added dropwise a solution of chlorotriethylsilane inTHF (1.0M, 1.11 mL). The mixture was warmed to room temperature andstirred at room temperature for about 1 hour. The solution was cooled toabout −78° C. To it was added dropwise a solution of butyllithium inhexane (1.6M, 694μL). The mixture was stirred at about −78° C. for about1 hour arid was warmed to about −15° C. during the following 30 min. Thesolution was cooled to about −78° C. To it was added dropwise of asolution of1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (150 mg)(see preparation #7) in THF (lmL). The solution was warmed to roomtemperature and stirred at room temperature for 19 hours. The solutionwas cooled to −78° C. To it were added dropwise methanesulfonyl chloride(163 mg), then, diisopropylethylamine (87 mg). The solution was warmedto room temperature in 1 hour and stirred at room temperature for 3hours. To the solution was added 4 mL of IN HCl aqueous solution and 4mL of THF. The solution was stirred at 0° C. for 1.5 hours. The organicsolvent was removed in vacuo. The aqueous solution was neutralized topH=8 by adding 6N KOH aqueous solution at 0° C. The aqueous solution wasextracted with DCM twice. The organic layers were combined and washedwith brine once, dried over MgSO₄, filtered and condensed in vacuo. Theresidue was purified by column chromatography on silica, eluting withCH₃Cl/MeOH/Et₃N, 98:2:0.1 The title compound was obtained as a solid, 44mg, yield: 25%. MS(ES) 525.2, Calc. MW=525.3.

Alternatively, the compound of Example 2,(±)-1-methylsulfonyl-(3-chlorophenyl)-5-[(4-chlorophenyl) hydroxyl(1-methyl-1H-imidazol-5-yl) methyl] indole was also made analogously tothe method described for making Example Y, using methanesulfonylchloride in place of 4-morpholinecarbonyl chloride. Yield: 77%. MS(Calc.): 526.46, MS(ES): 526.

The enantiomers of the title compound can be separated by using atechnique known in the art, such as preparative HPLC on a chiral column.

EXAMPLE 3(±)-1-(N,N-Dimethylcarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole

The title compound was synthesized analogously to the second methoddescribed for making Example 2, using dimethylcarbamyl chloride in placeof methanesulfonyl chloride. MS (electrospray):518.2; calc. MW: 518.5.

EXAMPLE 4(±)-1-Methylsulfonyl-3-(3-chlorophenyl)-5-[amino(4-chloro-phenyl)(1-methyl-1H-imidazol-5-yl)methyl]indole

Freshly distilled SOCl₂ (18 ml) was injected into(±)-1-methylsulfonyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-yl) methyl]indole (1) (1.74 g, 3.31 mmol, seeExample 2) under N₂ atmosphere and stirred at about 38° C. for about 21hrs. The mixture was evaporated to dryness in vacuo. 1.9 g of theintermediate,(±)-1-methylsulfonyl-3-(3-cholorophenyl)-5-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-yl)methyl]indole,was obtained and it was used in the following reaction without furtherpurification. The crude intermediate was taken into 15 ml THF andinjected into 45 mL of liquid NH₃ solution under N₂ at −78° C. Themixture was stirred for about 2 h and gradually warmed up to roomtemperature. The reaction solution was diluted by methylene chloride andfiltered. The filtrate was evaporated to dryness in vacuo. The crudeproduct was purified by flash chromatograph over silica gel, elutingwith a mixture of methylene chloride and MeOH (5/0.2). The purefractions were pooled and stripped down. The amine was converted intoHCl salt and recrystallized from CH₂Cl₂/hexane. The precipitate wasfiltered and dried under vacuum overnight, yielding 1.02 g (56%) of thetitle compound. MS (Calc.) 525.46, MS (ES):525.2.

EXAMPLE 7(±)-1-(1-Pyrrolidinecarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole

The title compound was synthesized analogously to the second methoddescribed for making Example 2, using 1-pyrrolidinecarbonyl chloride inplace of methanesulfonyl chloride. MS (electrospray):544.3; calc. MW:544.51.

EXAMPLE 11(±)-1-(N,N-Diethylcarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole

The title compound was synthesized analogously to the second methoddescribed for making Example 2, using diethylcarbamyl chloride in placeof methanesulfonyl chloride. MS (electrospray):546.2; calc. MW: 546.5.

EXAMPLE 21(±)-1-Acetyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole

The title compound was synthesized analogously to the first methoddescribed for making example 2, using acetic anhydride in place ofmethanesulfonyl chloride. MS(electrospray): 489.2; Calc. MW: 489.4.

EXAMPLE V(±)-1-Methylsulfonyl-2-chloro-3-(3-cholorophenyl)-5-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-yl)methyl]indole

The title compound was made analogously to the method described inExample 4, except that(±)-1-methylsulfonyl-3-(3-cholorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-yl)methyl]indole was reacted with thionyl chloride for about 3 days insteadof 21 hrs. Yield: 55%. MS (Calc.):559.91, MS (ES): 559.00.

EXAMPLE Y(+)-1-(4-Morroholinecarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)-hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole

A THF solution (75 ml) of 1-methylimidazole (5.28 ml, 66.12 mmol) wascooled down to about −78° C., to which 2.5 M n-butyllithium in hexane(28.25 ml, 70.628 mmol) was added under N₂ atmosphere. The mixture wasstirred for about 30 min at about −78° C., then 1M chlorotriethylsilane(69.13 ml, 69.13 mmol) in THF was added dropwise. The cooling bath wasremoved and the reaction solution was stirred for about another 2 hrs.Then it was cooled down to about −78° C. again, to which the same volumeof n-butyllithium solution was injected, and it was stirred for about 1hr and gradually warmed up to room temperature in about 40 min. Then itwas cooled down to about −78° C. for about 20 min, to which a THFsolution of 3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (5.5 g, 15.027mmol, see Preparation 8, below) was added and stirred for about 15 minat about −78° C. After the cooling bath was removed, the mixture wasstirred for about 0.5 hr and 130 ml of ether was added. The mixture wasstirred at about 57° C. under N₂ atmosphere overnight. TLC (CH₂Cl₂:MeOH5/0.6, AcOEt:Hexane 1:1) showed the reaction was complete. It was cooleddown to about 0 ° C. and 9 ml (75.14 mmol) of 4-morpholinecarbonylchloride was injected and stirred for about 5 hrs. It was quenched bysaturated NH₄Cl (100 ml×3). The organic layer was stripped down, and theresidue was taken into 250 ml CH₂Cl₂, which was washed with 2M HCl, (100ml×2), saturated NaHCO₃ (100 ml×2) and brine (100 ml×3). The organicsolution was dried over Na₂SO, and stripped down. The crude product waspurified by silica gel flash chromatograph, eluting with a mixturesolution of CH₂Cl₂ and methanol (5:0.25). The pure fractions were pooledand evaporated in vacuo to dryness. 7 g of the title compound wasobtained (yield 83%). MS (Calc.): 561.2, MS (ES): 561.2.

EXAMPLE Z(±)-1-(4-Morpholinecarbamoyl)-3-(3-cholorophenyl)-5-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]indole:

The title compound was made analogously to the method described formaking Example 4, using(±)-1-(4-morpholinecarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole(see Example Y) in place of(±)-1-methylsulfonyl-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxyl(1-methyl-1H-imidazol-5-yl)methyl]indole. Yield: 72%. MS (Calc.): 560.49, MS (ES): 560.30.

The following compounds can be synthesized analogously to the proceduresdetailed for Examples 1 to 4 but using the appropriate startingmaterials and modifications, which are well known to those of ordinaryskill in the art. Examples 5, 6, 6, 18, 20, 22, B, D, F, J, L, N, P, Rand X can be synthesized analogously to Example 4. Examples 9, 15, 17,19, A, C, E, I, K, M, O, Q and W can be synthesized analogously toExample 2. Example U can be synthesized analogously to Example V.

Examples 13 and 14 were obtained by reacting the compound of Preparation8, below, with iodomethane in the presence of K₂CO₃ in DMF at about 80°C. for about 5 hrs. The resulting intermediate (where Y is methyl, seetable of Examples below) was divided into two lots. One lot wassubjected to an synthetic scheme analogous to the first proceduredescribed for Example 2 except the step of reacting it withmethanesulfonyl chloride was not conducted, to obtain the compound ofExample 13. The other lot of the intermediate was subjected to asynthetic scheme analogous to Example 4 to obtain the compound ofExample 14.

Example No. Z Y R¹⁰  1 H H OH  2 H —S(O)₂—CH₃ OH  3 H —C(O)—N(CH₃)₂ OH 4 H —S(O)₂—CH₃ NH₂  5 H H NH₂  6 H —C(O)—N(CH₃)₂ NH₂  7 H

OH  8 H

NH₂  9 H —S(O)₂-Phenyl OH 10 H —S(O)₂-Phenyl NH₂ 11 H —C(O)—N(CH₂CH₃)₂OH 12 H —C(O)—N(CH₂CH₃)₂ NH₂ 13 H —CH₃ OH 14 H —CH₃ NH₂ 15 H

OH 16 H

NH₂ 17 H

OH 18 H

NH₂ 19 H

OH 20 H

NH₂ 21 H —C(O)—CH₃ OH 22 H —C(O)—CH₃ NH₂ A H —S(O)₂—CF₃ OH B H—S(O)₂—CF₃ NH₂ C H —S(O)₂—CH₂—CF₃ OH D H —S(O)₂—CH₂—CF₃ NH₂ E H

OH F H

NH₂ I H

OH J H

NH₂ K H

OH L H

NH₂ M H

OH N H

NH₂ O H —C(O)—NH₂ OH P H —C(O)—NH₂ NH₂ Q H

OH R H

NH₂ U Cl

NH₂ V Cl —S(O)₂—CH₃ NH₂ W H

OH X H

NH₂ Y H

OH Z H

NH₂

Preparation 1: 2-(3-Chlorophenyl)-N-methoxy-N-methyl-acetamide

A solution of 3-chlorophenylacetic acid (5.00 g, 29.3 mmol),1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide HCL (6.18 g, 32.2 mmol),and 1-hydroxybenzotriazole (HOBt; 4.00 g, 29.3 mmol) in dichloromethane(DCM; 40 mL) was stirred at room temperature for about 10 minutes. Thesolution was cooled to about 0° C. To it were addedN,O-dimethylhydroxylamine HCl (2.86 g, 29.0 mmol) anddiisopropylethylamine (DIEA; 3.80 g, 29.3 mmol). The reaction mixturewas warmed to room temperature and stirred for about 5 hours. Thesolution was diluted with 100 mL of DCM and washed with saturated NaHCO₃aqueous solution (2 times), 1N HCl aqueous solution (2 times) and brine(2 times), dried over anhydrous MgSO₄, filtered and concentrated invacuo. The liquid obtained was purified by column chromatography onsilica eluting with EtOAc/hexane 1:1. The title compound was obtained ascolorless liquid. Yield: 5.60 g, 89%. Rf=0.44 (silica, EtOAc/hexane1:1). ¹H NMR (300 MHz, CDCl₃) 7.18-7.34 (m, 4H), 3:76 (S, 2H), 3.66 (S,3H), 3.22 (S, 3H).

Preparation 2: 2-(3-Chlorophenyl)-acetaldehyde

A suspension of LiAlH₄ (1.90 g, 51 mmol) in anhydrous ether (250 mL) wasstirred at room temperature under nitrogen for about 1 hour. Thesuspension was cooled to about −45° C. To it was added drops of asolution of 2-(3-chlorophenyl)-N-methoxy-N-methyl-acetamide (8.19 g,38.3 mmol, see Preparation 1) in 10 mL of anhydrous tetrahydrofuran(THF). The mixture was warmed to about 0° C. and stirred for about 3hours. The solution was then cooled to about −45° C. To this solutionwas slowly added a solution of KHSO₄ (13 g) in water (about 30 mL) theresulting mixture was filtered through CELITE®. The filtrate wasconcentrated in vacuo, the resulting solution was diluted with DCM andwashed with 1N HCl aqueous solution (2 times), and brine (2 times) driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The titlecompound was obtained as a liquid (5.80 g), which was used immediatelyin the next step without further purification. Rf=0.71 (silica,EtOAc/hexane 1:3).

Preparation 3: 3-(3-Chlorophenyl)indole

A solution of 2-(3-chlorophenyl)-acetaldehyde (5.80 g, 37.5 mmol) andphenylhydrazine (6.22 g, 57.5 mmol) in glacial acetic acid (150 mL) wassaturated with nitrogen by bubbling N₂ through the solution. Thesolution was then refluxed for about 2.5 hours. Solvent was removed invacuo and the residue obtained was dissolved in DCM and washed with 1NHCl aqueous solution (2 times), saturated NaHCO₃ aqueous solution (2times) and brine (2 times), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica, eluting with EtOAc/hexane 1:6. The titlecompound was obtained as a reddish oil. Yield: 5.30 g, 62%. Rf=0.26(silica, EtOAc/hexane 1:4)

Preparation 4: 3-(3-Chlorophenyl)-indoline

3-(3-Chlorophenyl)indole (5.30 g, 23.3 mmol) was dissolved in 50 mL of 1M BH₃ in THF. The mixture was cooled to about 0° C. To the solution wasadded slowly TFA (50 mL). After addition, the solution was stirred forabout 10 minutes. To the solution was added slowly 1M BH₃ in THF (40mL). The mixture was stirred for about 5 minutes and then concentratedin vacuo. The residue was purified by column chromatography on silica,eluting with EtOAc/hexane 1:6. The title compound was obtained as an oil(Yield; 3.93 g, 74%). Rf=0.20 (Silica, EtOAc/hexane 1:4) MS (ES): 229.1;Calc. MW=229.7.)

Preparation 5: 1-Methylsulfonyl-3-(3-chlorophenyl)indoline

To a solution of 3-(3-chlorophenyl)indoline (3.88 g, 16.9 mmol) and DIEA(2.40 g, 18.6 mmol) in DCM (40 mL) was added dropwise methanesulfonylchloride (2.13 g, 18.6 mmol) at about 0° C. The mixture was stirred forabout 1.5 hours. The solution was diluted with DCM and washed withsaturated NaHCO₃ solution (2 times), 1N HCl aqueous solution (2 times)and brine (2 times) and dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica, eluting with EtOAc/hexane 1:4. The titlecompound was obtained as an oil Yield: 4.40 g, 85%. Rf=0.41, silica,EtOAc/hexane 1:2. ¹H NMR (300 MHz, CDCl₃) δ: 7.52 (d, 1H), 7.24-7.34 (m,3H), 7.20 (s, 1H), 7.02-7.14 (m, 3H), 4.59 (t, 1H), 4.38 (t, 1H), 3.87(dd, 1H), 2.92 (s, 3H).

Preparation 6:1-Methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline

To a solution of 1-methylsulfonyl-3-(3-chlorophenyl)indoline (4.40 g,14.3 mmol, see Preparation 5) and 4-chlorobenzoyl chloride (3.25 g, 18.6mmol) in CS₂ (25 mL) was added portionwise AlCl₃ (7.62 g, 57.2 mmol) atabout 0° C. A brown precipitate formed immediately. The mixture wasstirred for about 2 hours. To the mixture was added slowly 100 mL ofcold water containing 3 mL of concentrated HCl. The solution was dilutedwith DCM and the organic layer was separated and washed with 1N HClaqueous solution (2 times), saturated NaHCO₃ aqueous solution (2 times)and brine (2 times), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography on silica, eluting with EtOAC/hexane 1:2. The titlecompound was obtained as a solid. Yield=3.90 g, 61%. Rf=0.24 (silica,EtOAc/hexane 1:2). MS (ES): 445.2; Calc. MW=445.4, ¹H NMR (300 MHz,CDCl₃) δ: 7.67-7.76 (m, 3H), 7.53-7.59 (m, 2H), 7.48 (s, 1H), 7.44 (s,1H), 7.30-7.32 (m, 2H), 7,20 (m, 1H), 7.09-7.14 (m, 1H), 4.65 (t, 1H),4.50 (t, 1H), 3.98 (dd, 1H), 3.02 (s, 3H).

Preparation 7:1-Methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole

A solution of1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline (350 mg)and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (356 mg) in dioxane (6 mL)was refluxed under N₂ for about 6 hours and then heated at about 95° C.overnight. The solvent was removed. The residue was purified by columnchromatography on silica, eluting with EtOAc/hexane, 1:4. The titlecompound was obtained as a solid. MS(ES): 443.2, calc. Mw=443.4.Rf=0.38, silica, EtOAc/hexane, 1:2. 195 mg, yield: 56%.

Preparation 8: 3-(3-Chlorophenyl)-5-(4-chlorobenzoyl)indole

To a solution of1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (11.44 g,25.76 mmol, see Preparation 7) in anhydrous THF (150 ml) was addedtetrabutylammonium fluoride (33.5 ml, 1.0 M solution in THF). Theresulting solution was refluxed under nitrogen for about 3 hrs. Thesolvent was removed under reduced pressure. The residue was dissolved inEtOAc and washed with 1N HCl (2 times), saturated NaHCO₃ aqueoussolution (2 times) and brine (2 times), dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica, eluting with EtOAc/hexane 1:4. The titlecompound was obtained as a yellow solid. Yield=8.1 g, 86%.

What is claimed is:
 1. A method of treating a tumor, fibrosis,restenosis, neoplasm, fungal infection, arteriosclerosis, carcinoma,benign tumor, retina disease, hepatitis, renal disease, myeloidleukemia, viral infection, nervous system tumor, viral infection, breasttumor, pancreas tumor, or brain tumor in a subject in need thereof,which comprises administering to said subject an effective amount of acompound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein ———————represents an optional bond; m, n, p, and q are each independently 0 or1; T for each occurrence is independently selected from the groupconsisting of CR²⁶R²⁷, S, O, C(O), S(O)₂ and NR²⁸; X is N—Y, O or Swhere Y is selected from the group consisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷,S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵,S(O)NR²⁹R³⁰, and S(O)₂NR³¹R³²; Z is selected from the group consistingof H, cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸ and C(O)R¹⁹; R¹, R²,R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ and R²⁷ are eachindependently selected from the group consisting of H, halo, hydroxy,thio, and cyano, or an optionally substituted moiety selected from thegroup consisting of alkyl, akenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio,arylthio, alkylamino, arylamino and alkyl carbonyl amino; or R¹ and R²when on adjacent positions, or R⁴ and R⁵, or R¹¹ and R¹², are takentogether to form a bivalent radical selected from the group consistingof —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH═CH—, —OCH₂—CH₂—, —O—CH₂—CH₂—CH₂— and—CR³³═CR³⁴—CR³⁵═CR³⁶—; R⁷, R⁸, and R⁹ are each independently selectedfrom the group consisting of H, halo, aryl, alkyl, substituted alkyl,alkyloxy, alkylthio, aryloxy, arylthio amino, mono- or di-alkylamino,hydroxycarbonyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl,cyanoarylalkyl, arylalkyl and substituted arylalkyl; R¹⁰ is selectedfrom the group consisting of H, amino, azido, hydroxy, halo, alkyl,substituted alkyl, cyano, hydroxyalkyl, hydroxycarbonyl, aminoalkyl,mono- or di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy,alkylcarbonylalkyl, cyanoalkyl, alkyloxycarbonylalkyl, carboxyalkyl,cycloalkyl, cycloalkylamino, cycloalkylhydroxy, imidazoyl, substitutedimidazoyl, aminocarbonylalkyl, aryloxy, thio, alkylthio, OS(O₂)R¹⁸,OC(O)R¹⁹, OC(O)NR²⁰R²¹, OC(S)NR²²R²³, OS(O)NR²⁹R³⁰, OS(O)₂NR³¹R³² andaryl thio; and R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵, R²⁸, R²⁹,R³⁰, R³¹, R³² and R³⁷ for each occurrence are each independentlyselected from the group consisting of H, alkyl, substituted alkyl,alkenyl, cycloalkyl, aryl and arylalkyl; or R²⁰ and R²¹, or R²² and R²³,or R²⁹ and R³⁰, or R³¹ and R³² are taken together to form a bivalentradical selected from the group consisting of—(CH₂)_(r)—NR³⁷—(CH₂)_(s)—, —(CH₂)_(r)—O—(CH₂)_(s)— and —(CR³⁸R³⁹)_(t)—,where r and s are each independently 1 to 3 and t is 2 to 6; R³³, R³⁴,R³⁵, R³⁶, R³⁸ and R³⁹ are each independently selected from the groupconsisting of H, halo, cyano, alkyl, substituted alkyl aryl, substitutedaryl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino,hydroxy and thio.
 2. A method of treating a tumor, fibrosis, restenosis,neoplasm, fungal infection, arteriosclerosis, carcinoma, benign tumor,retina disease, hepatitis, renal disease, myeloid leukemia, viralinfection, nervous system tumor, viral infection, breast tumor, pancreastumor, or brain tumor in a subject in need thereof, which comprisesadministering to said subject an effective amount of a compound offormula (II):

or a pharmaceutically acceptable salt thereof, wherein ———————represents an optional bond, provided that only one of the optionalbonds is present in a compound of formula (I); m, n, p, and q are eachindependently 0, 1, or 2; T¹, T², T³ and T⁴ for each occurrence are eachindependently selected from the group consisting of CR²⁶R²⁷, S, O, C(O),S(O)₂ and NR²⁸; X is N—Y, O or S where Y is selected from the groupconsisting of H, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹,C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³²; Z isselected from the group consisting of H, hydroxy, alkoxy, aryloxy,cyano, halo, CR¹⁴R¹⁵R¹⁶, S(O)R¹⁷, S(O)₂R¹⁸, C(O)R¹⁹, C(O)NR²⁰R²¹,C(O)OR²⁴, C(S)NR²²R²³, C(S)OR²⁵, S(O)NR²⁹R³⁰ and S(O)₂NR³¹R³², providedthat when the optional bond connected to Z is present then Z is oxygenor sulfur; R¹, R², R³, R⁴, R⁵, R⁶, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁶ andR²⁷ for each occurence are each independently selected from the groupconsisting of H, halo, hydroxy, thio, and cyano, or an optionallysubstituted moiety selected from the group consisting of alkyl, akenyl,alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy,aryloxy, alkylthio, arylthio, alkylamino, arylamino and alkyl carbonylamino; or each pair of R¹ and R², R⁴ and R⁵, and R¹¹ and R¹², when onadjacent positions, is independently taken together to form a bivalentradical selected from the group consisting of —O—CH₂—O—, —O—CH₂—CH₂—O—,—O—CH═CH—, —O—CH₂—CH₂—, —O—CH₂—CH₂—CH₂— and —CR³³═CR³⁴—CR³⁵═CR³⁶—; R⁷,R⁸, and R⁹ are each independently H, halo, amino, cyano,hydroxycarbonyl, or an optionally substituted moiety selected from thegroup consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy, arylthio,alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl, cyanoarylalkyl, andarylalkyl, provided that when R⁷, R⁸, or R⁹ is bound to one of thenitrogen atoms of the imidazolyl ring, R⁷, R⁸, or R⁹ is H or anoptionally substituted moiety selected from the group consisting ofaryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O)₂-alkyl,cyanoarylalkyl, and arylalkyl; R¹⁰ is selected from the group consistingof H, amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano,hydroxycarbonyl, mono- or di-alkylamino, alkyloxy, cycloallyl,cycloalkylamino, cycloalkyloxy, imidazolyl, substituted imidazolyl,aryloxy, thio, alkylthio, arylthio, OS(O₂)R¹⁸, OC(O)R¹⁹, OC(O)NR²⁰R²¹,OC(S)NR²²R²³, OS(O)NR²⁹R³⁰ and OS(O)₂NR³¹R³²; R¹⁷ and R¹⁸, for eachoccurrence are each independently H, OH or an optionally substitutedmoiety selected from the group consisting of alkyl, alkenyl, cycloalkyl,aryl, arylalkyl and heterocyclyl; R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴, R²⁵,R²⁸, R²⁹, R³⁰, R³¹, and R³² for each occurrence are each independently Hor an optionally substituted moiety selected from the group consistingof alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl; or eachpair of R²⁰ and R²¹, or R²² and R²³, or R²⁹ and R³⁰, and R³¹ and R³² isindependently taken together to form a bivalent radical selected fromthe group consisting of —(CH₂)_(r)—NR⁴⁰—(CH₂)_(s)—,—(CH₂)_(r)—O—(CH₂)_(s)—, —(CR³⁸R³⁹)_(t)—, and—(CH₂)_(r)—NR⁴⁰—(C(O))_(u)— where r and s are each independently 1 to 3,t is 2 to 6 and u is 1 or 2; R³³, R³⁴, R³⁵, R³⁶, R³⁸ and R³⁹ for eachoccurrence are each independently selected the group consisting of H,amino, halo, cyano, alkyl, substituted alkyl aryl, substituted aryl,alkyloxy, aryloxy, alkylthio, arylthio, mono- or di-alkylamino,arylamino, hydroxy, heterocyclyl and thio; and R⁴⁰ is H, S(O)₂R¹⁸,C(O)R¹⁹, C(O)NR²⁰R²¹, C(S)NR²²R²³, C(O)OR²⁴, C(S)OR²⁵, and S(O)₂NR³¹R³²,or an optionally substituted moiety selected from the group consistingof alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.